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Dysregulated Adiponectin Transmembrane Signaling in Diabetic CoronaryVascular Injury and Heart Failure

Award Number: R01HL157495
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Dysregulated Adiponectin Transmembrane Signaling in Diabetic CoronaryVascular Injury and Heart Failure - With extensive application of treatment strategies, the acute mortality of patients having myocardial infarct (MI) has significantly reduced but these patients turn to ischemic cardiomyopathy (IC). Importantly, the incidence of IC is much higher in diabetic patients, a major risk factor for cardiovascular disease. Despite the major advances in cardiac interventions, diabetic IC (DIC) morbidity and mortality continue to rise. It is increasingly recognized that integrative approaches, rather than purely focusing on cardiomyocytes, must be undertaken for DIC prevention/treatment. Supplementation of adiponectin (APN), a protein identified as an adipokine, protects the acute ischemic heart in animal model. However, several clinical studies demonstrate that elevated APN levels are strongly associated with poor prognosis of chronic HF. We and others previously report that APN function is markedly attenuated in diabetic animals and patients. Our most recent study demonstrates that diabetes injures heart not only on cardiomyocytes, the impaired coronary endothelial cells (EC) in diabetes leading to microcirculation dysfunction dramatically enhancing cardiac dysfunction. Our recently published work and preliminary experiments further demonstrate that 1) in human diabetic coronary EC, APN receptor 1 knockout (AdipoR1, prototypic APN receptor in EC) mRNA expression is unchanged, but AdipoR1 protein expression is significantly reduced; 2) coronary vascular dysfunction (CVDy) is markedly exaggerated in diabetic animals as well as in AdipoR1KO mice; in type 2 diabetic mice, AdipoR1 expression is significantly reduced in the coronary EC. 3) proteomics reveal that AdipoR1 phosphorylation is the most significant post-translational modification in diabetic coronary EC; 4) GRK5 (not GRK2), the prototypical GRK family member in EC, is markedly upregulated in diabetic coronary EC; 5) GRK5OE in coronary EC has no effect upon AdipoR1 mRNA expression. However, GRK5OE largely reproduces the pathologic phenotypes in human coronary EC concerning APN/AdipoR1 signaling; 6) conversely, GRK5KO restores APN angiogenic effect in diabetic coronary EC. Based upon these exciting preliminary results, we will test a novel hypothesis that diabetic GRK5 upregulation and resultant AdipoR1 phosphorylation plays causative roles in diabetic CVDy and contributes to the deleterious consequences of DIC. GRK5-AdipoR1 system may be a novel therapeutic target against diabetic CVDy, ultimately ameliorating the DIC. This hypothesis will be rigorously tested by addressing the following 3 scientific questions: 1) what is the molecular mechanism that causes AdipoR1 desensitization and blocks AdipoR1 function in diabetes? (Aim 1); 2) How is APN’s coronary vascular protective action impaired when AdipoR1 is phosphorylated? (Aim 2), and 3) which intervention is most effective in restoring coronary vascular function in the diabetic heart against DIC? (Aim 3). Successful completion of proposed studies will greatly advance our knowledge in understanding the basis of diabetic cardiac injury through integrating regulation of coronary microcirculatory function, and identify novel therapeutic targets against DIC.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $487,072 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	4	1/17/2025	NON-COMPETING CONTINUATION	$487,072
														Subtotal = $487,072

Issue Date FY: 2024 ( Subtotal = $931,446 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	3	1/15/2024	NON-COMPETING CONTINUATION	$491,531
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	3	6/21/2024	NON-COMPETING CONTINUATION	$43,692
2024	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	003	2	7/25/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$519,881
2024	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	002	1	7/25/2024	NEW	-$123,658
														Subtotal = $931,446

Issue Date FY: 2023 ( Subtotal = $155,577 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	001	2	2/6/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$551,800
2023	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	002	1	5/15/2023	NEW	-$396,223
2023	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	1	2/3/2023	NEW	$0
														Subtotal = $155,577

Issue Date FY: 2022 ( Subtotal = $624,478 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	1	1/28/2022	NEW	$624,478
														Subtotal = $624,478

Grand Total All Awards = $2,198,573

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Dysregulated Adiponectin Transmembrane Signaling in Diabetic CoronaryVascular Injury and Heart Failure

Award Number: R01HL157495

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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